Long-Term Interferon-α Treatment in Essential Thrombocythemia

Background: Essential thrombocythemia (ET) is a chronic myeloid stem cell disorder characterized by an uncontrolled production of platelets. Common complications are recurring thrombotic events and/or haemorrhage. Although ET is in general associated with good prognosis, prognostically adverse events such as fibrotic or leukemic transformation occur at an increasing risk in patients with long disease duration. Since interferon-α (IFN-α) harbors the potential of inducing molecular remission in approximately 20% of ET patients as demonstrated by JAK2 V617F, the drug may prolong the natural course of the disease. Therefore, in particular younger ET patients are likely to benefit from long-term IFN-α treatment. Since data on long-term effects of IFN-α treatment are scarce, we here report on safety, efficacy, and molecular markers from ET high-risk patients being treated with IFN-α at our institution for up to 21 years.

Results: Within 12 months (Jan 2014 – Dec 2014), 73 ET patients at the median age of 61 years (range 31-97) presented for regular follow-up at our out-patient clinic. All patients have given informed consent for data evaluation according to the Declaration of Helsinki. Eighty-one percent (59/73) were high-risk characterized by the presence of ≥1 of the following risk factors: i) age >60 years, ii) previous thrombosis, or iii) platelet count >1.500/nL. All high-risk patients received cytoreductive therapy: Hydroxyurea (HU) was the most frequent drug administered at last follow-up (27/59, 46%), followed by IFN-α (18/59, 30%), anagrelide (11/59, 19%), or HU plus anagrelide (3/59, 5%). At the time of data evaluation, no ET patient was treated with an approved or experimental drug within a clinical study. Of the 59 high-risk patients, a total number of 27 patients (46%) were currently (n=18) or previously (n=9) treated with IFN-α (conventional IFN-α, n=3; pegylated IFN-α, n=24). Median age of the total IFN-α cohort was 54 years (range 40-85). Main reasons for IFN-α initiation in these patients were previous thrombosis (n=16, 59%) and high platelet count (n=7, 26%), followed by age >60 years (n=4, 15%). Interestingly, one third of patients (9/27) received IFN-α as a long-term therapy for 10-21 years. IFN-α was discontinued in the 9 previously treated patients after a median treatment time of 71 months (range 1-206). Main reasons for discontinuation were depression/fatigue (n=3), arthralgia (n=2), diarrhea/nausea (n=2), lack of response (n=1), or myocardial infarction (n=1). Of note, the myocardial infarction represented a thromboembolic event and occurred in complete hematologic remission under long-term treatment with IFN-α (206 months). No further vascular events were recorded under IFN-α therapy. Given a total observation time of 211 patient years, the vascular complication rate in our IFN-α cohort is 0.13 per patient and year. Furthermore, no disease progression to secondary myelofibrosis or acute myeloid leukemia occurred during the whole observation period. Since JAK2 V617F had been identified in the year 2005, peripheral blood from all ET patients presenting at our out-patient clinic was preserved. In approximately one half of the 27 patients, IFN-α treatment was initiated before (n=14, 52%) or after (n=13, 48%) the year 2005. Mutation testing in the earliest samples available from each patient revealed mutation frequencies of JAK2 V617F, MPL W515L, and CALR of 52% (14/27), 0% (0/27), and 30% (8/27) in the total IFN-α population. Interestingly, patients under long-term treatment with IFN-α (10-21 years) were either triple-negative (n=3) or CALR mutated (n=6) at the sensitivity limit of DNA-based fragment analysis (~1%). Serial quantification of the JAK2 V617F allele burden before and under IFN-α could be performed in 10 patients and showed a decrease from 10.5% (5-27%) to 2.9% (0.1-22%) at the last follow-up (p= .004).

Conclusions: We conclude from our data that long-term treatment with IFN-α for 10 years or more is feasible in approximately one third of high-risk ET patients. In our patients receiving IFN-α, vascular complications were restricted to a single event in an observation time of 211 patient years, whereas no disease progressions to secondary myelofibrosis or acute myeloid leukemia occurred. Controlled clinical trials are warranted to prove the long-term benefit of IFN-α treatment in high-risk ET.